The ability of a substance to exist in more than one crystalline form is defined as polymorphism and these different crystalline forms are named “polymorph modifications” or “polymorphs”. In general, polymorphism is caused by the ability of the molecule of a substance to change its conformation or to form different intermolecular and intramolecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs.
The different polymorphs of a substance possess different energies of the crystal lattice and, thus, they show different physical properties of the solid state such as form, density, melting point, colour, stability, dissolution rate, milling facility, granulation, compacting etc., which in medicaments may the preparation of pharmaceutical forms, their stability, dissolution and bioavailability and, consequently, their action.
Polymorphism of medicaments is the object of studies of interdisciplinary expert teams [J. Haleblian, W. McCrone, J. Pharm. Sci. 58 (1969) 911; L. Borka, Pharm. Acta Helv. 66 (1991) 16; M. Kuhnert-Brandstatter, Pharmazie 51 (1996) 443; H. G. Brittain, J. Pharm. Sci. 86 (1997) 405; W. H. Streng, DDT 2 (1997) 415; K. Yoshii, Chem. Pharm. Bull. 45 (1997) 338, etc.]. A good knowledge of polymorphism represents a precondition for a critical observation of the whole process of medicament development. Thus, at deciding on the production of a pharmaceutical form in solid state and with regard to the dose size, stability, dissolution and anticipated action, it is important to determine the existence of all solid state forms (on the market some computer programs can be found, e.g. >>Polymorph<< as a module of >>Cerius2<< program, MSI Inc., USA) and to determine the physical-chemical properties of each of them. Only on the basis of these determinations can the most appropriate polymorph be selected for the development of pharmaceutical formulations of desired properties.
The compound (S)-3-aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol is disclosed in the form of its hydrochloride salt in U.S. patent application Ser. No. 12/142,692 and has the following chemical structure:
(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol has shown promise as an antibacterial agent, especially against Gram negative pathogens. Changes to the solid form of this compound that are capable of improving its physical and/or chemical stability gives a significant advantage over less stable forms of the same compound. The present invention advantageously provides one or more of those advantages and provides further related advantages.